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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Coronary flow reserve is reduced in patients with idiopathic dilated cardiomyopathy (DCM). We examined acute effects of intracoronary enalaprilat on metabolic coronary vasodilation during pacing tachycardia in patients. Coronary blood flow (Doppler guidewire) and diameter (quantitative angiography) were measured in seven patients with DCM and seven control subjects. In the DCM group, tachypacing increased coronary blood flow by 37 +/- 22% from the baseline before enalaprilat and by 65 +/- 22% (p < 0.01 vs. before treatment) after enalaprilat (0.5 microg/kg/min for 5 min, i.c.) at comparable double product. Pacing-induced dilation of the epicardial coronary artery also was greater after enalaprilat (p < 0.05). Effects of enalaprilat on coronary blood flow and diameter during pacing tachycardia were abolished by pretreatment with intracoronary administration of the nitric oxide (NO) synthesis inhibitor, N(G)-monomethyl-L-arginine. These beneficial effects of enalaprilat on large and small coronary vasodilation were not observed in control patients. Thus, intracoronary enalaprilat acutely augmented dilator responses of the large and small coronary arteries to pacing tachycardia in patients with DCM, and NO appeared to play an important role in mediating the effects of enalaprilat. These favorable effects of enalaprilat on the coronary circulation may be of clinical significance in patients with heart failure due to nonischemic DCM. Further long-term studies of the effects of angiotensin-converting enzyme inhibition on coronary vasodilation will be needed in this population.
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PMID:Intracoronary enalaprilat improves metabolic coronary vasodilation in patients with idiopathic dilated cardiomyopathy. 1067 57

Although the role of nitric oxide (NO) in the modulation of vascular tone has been studied and well understood, its potential role in the control of myocardial metabolism is only recently evident. Several lines of evidence indicate that NO regulates myocardial glucose metabolism; however, the details and mechanisms responsible are still unknown. The aim of this study was to further define the role of NO in the control of myocardial glucose metabolism and the nitric oxide synthase (NOS) isoform responsible using transgenic animals lacking endothelial NOS (ecNOS). In the present study, we examined the regulation of myocardial glucose uptake using isometrically contracting Langendorff-perfused hearts from normal mice (C57BL/6J), mice with defects in the expression of ecNOS [ecNOS (-/-)], and its heterozygote [ecNOS (+/-)], and wild-type mice [ecNOS (+/+)] (n=6, respectively). In hearts from normal mice, little myocardial glucose uptake was observed. This myocardial glucose uptake increased significantly in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME). Similarly, in the hearts from ecNOS (-/-), glucose uptake was much greater than in normal mice, whereas myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice was not different from normal mice. In addition, myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice increased significantly in the presence of L-NAME. At a workload of 800 g. beats/min, L-NAME increased glucose uptake from 0.1+/-0.1 to 3+/-0.4 microg/min x mg in ecNOS (+/-) mice and from 0.2+/-0.1 to 2.7+/-0.7 microg/min x mg in ecNOS (+/+) mice. Furthermore, in the hearts from ecNOS (-/-) mice, 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cGMP), a cGMP analog or S-nitroso-N-acetylpenicillamine (SNAP), a NO donor essentially shut off glucose uptake, and in hearts from ecNOS (+/-) mice, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), an inhibitor of cGMP, increased the glucose uptake significantly. These results indicate clearly that cardiac NO production regulates myocardial glucose uptake via a cGMP-dependent mechanism and strongly suggest that ecNOS plays a pivotal role in this regulation. These findings may be important in the understanding of the pathogenesis of the diseases such as ischemic heart disease, heart failure, diabetes mellitus, hypertension, and hypercholesterolemia, in which NO synthesis is altered and substrate utilization by the heart changes.
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PMID:Myocardial glucose uptake is regulated by nitric oxide via endothelial nitric oxide synthase in Langendorff mouse heart. 1067 77

The production of endogenous nitric oxide, which regulates myocardial oxygen consumption, is decreased in heart failure. As with angiotensin-converting enzyme (ACE) inhibitors, amlodipine, a calcium antagonist, increases kinin-mediated nitric oxide production in coronary microvessels. We investigated the possibility of synergy between ACE inhibitors and amlodipine in regulating myocardial oxygen consumption. Left ventricular myocardium was isolated from 6 healthy dog hearts and 5 human hearts with end-stage heart failure at the time of orthotopic heart transplantation. Myocardial oxygen consumption was measured before and after administration of bradykinin, S-nitroso N-acetyl penicillamine (SNAP, a nitric oxide donor), ramiprilat (an ACE inhibitor), amlodipine, and the combination of a sub-threshold dose of ramiprilat (10(-8) md/L) + amlodipine. These experiments were repeated with L-nitro-arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthesis), dichloroisocoumarin (an inhibitor of kinin synthesis), and HOE 140 (a B2 kinin-receptor antagonist). Baseline myocardial oxygen consumption in canine hearts was 182 +/- 21 nmol/g/min. Bradykinin and SNAP caused dose-dependent reductions in myocardial oxygen consumption (p <0.05). Ramiprilat and amlodipine caused a 10 +/- 3.2% and 11 +/- 0.8% reduction in myocardial oxygen consumption, respectively, when used alone (p <0.05). In the presence of a subthreshold dose of ramiprilat, amlodipine caused a larger (15 +/- 1.7%) reduction in myocardial oxygen consumption compared with either drug used alone (p <0.05). In human hearts, baseline myocardial oxygen consumption was 248 +/- 57 nmol/g/min. Amlodipine caused a larger reduction in myocardial oxygen consumption when used with ramiprilat (22 +/- 3.2%) as compared with amlodipine alone (15 +/- 2.6%). The effect of both drugs was attenuated by L-NAME, dichloroisocoumarin, and HOE 140 (p <0.05). In conclusion, ACE inhibitors and amlodipine act synergistically to regulate myocardial oxygen consumption by modulating kinin-mediated nitric oxide release, and this combination of drugs may be useful in the treatment of heart failure.
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PMID:Synergy of amlodipine and angiotensin-converting enzyme inhibitors in regulating myocardial oxygen consumption in normal canine and failing human hearts. 1075 May 96

It remains controversial whether basal nitric oxide (NO) production in coronary resistance vessels in heart failure is enhanced or not. A transonic Doppler flow probe was placed around the left anterior descending coronary artery, and complete atrioventricular block was produced in fifteen dogs. The coronary pressure-flow relationships during long diastole were analyzed without and with pacing-induced heart failure. Three weeks after pacing at 240/min, plasma norepinephrine and renin activity significantly rose. Right atrial pressure and left ventricular end-diastolic pressure increased, and cardiac output and coronary perfusion pressure decreased; however, mean coronary blood flow did not change after pacing (55 +/- 5 to 52 +/- 5 ml/min/100 g, mean +/- SEM). The slope of the diastolic coronary pressure-flow relationship became steeper (1.22 +/- 0.13 to 1.62 +/- 0.09 ml/min/100 g/mmHg, p < 0.05) with a slight increase in the measured zero-flow pressure (29.5 +/- 1.1 to 32.8 +/- 1.5 mmHg, p < 0.05) after pacing. After pretreatment with indomethacin, administration of NG-nitro-L-arginine methyl ester caused an equal increase in the zero-flow pressure before (31.4 +/- 1.7 to 39.2 +/- 2.2 mmHg, p < 0.05) and after heart failure (33.9 +/- 2.5 to 41.6 +/- 2.2 mmHg, p < 0.05), and more decline of the slope of the coronary pressure-flow relationship in heart failure (1.86 +/- 0.22 to 1.20 +/- 0.05 ml/min/100 g/mmHg, p < 0.05) than before heart failure (1.11 +/- 0.12 to 1.05 +/- 0.11 ml/min/100 g/mmHg, N.S.). This indicates that in failing hearts the vasodilatory action of NO in small vessels predominates despite the presence of several vasoconstricting factors. These results suggest that coronary blood flow is maintained despite detrimental hemodynamic and activated neurohumoral factors in the initial stage of heart failure, and that increased basal NO production plays a central role in the maintenance of basal coronary blood flow.
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PMID:Augmented basal nitric oxide production contributes to maintenance of coronary blood flow in dogs with pacing-induced heart failure. 1088 83

Patients with heart failure exhibit impaired endothelium-dependent vasodilation. Although brief intraarterial administration of L-arginine improves endothelium-dependent vasodilatation in these patients, long-term oral supplementation is ineffective. To resolve these conflicting findings, we examined the effect of a single, short-term oral dose of L-arginine on serial, hourly forearm vascular responses to acetylcholine, sodium nitroprusside, and norepinephrine. Eighteen patients with heart failure were randomly allocated in a double-blinded, crossover study to receive either a single 20-g oral dose of L-arginine or placebo. Vascular responses were measured by forearm venous occlusion plethysmography before and at 60, 120, and 180 min after dosage. Blood was obtained for measurement of L-arginine and nitric oxide metabolite levels. Oral L-arginine increased plasma levels by fourfold at 60, 120, and 180 min. Vasodilatation to acetylcholine, 37 microg/min, was significantly enhanced at 60 min (percentage increase in forearm blood flow: placebo, 413 +/- 64%; L-arginine, 587 +/- 94%; p < 0.05), discernible at 120 min (p = 0.058) but no longer apparent at 180 min. Neither basal forearm blood flow, sodium nitroprusside, nor norepinephrine responses nor plasma levels of nitrite and nitrate were altered. We conclude that although short-term oral supplementation with L-arginine produced marked sustained elevation of plasma levels of L-arginine in patients with heart failure, responses to acetylcholine were only transiently improved.
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PMID:Transient improvement of acetylcholine responses after short-term oral L-arginine in forearms of human heart failure. 1089 57

The aims of this study were to (a) determine whether inducible nitric oxide synthase (iNOS) is expressed in small mesenteric arteries from rats with chronic heart failure (CHF), (b) investigate the functional significance of this potential source of nitric oxide (NO) on vascular responsiveness and (c) investigate the role that superoxide plays in modulating vascular function in these arteries. CHF was induced in male Wistar rats by coronary artery ligation (CAL). In sham-operated rats the ligature was not tied but pulled under the artery. Six weeks after surgery CAL rats had left ventricular (LV) infarctions and elevated LV end-diastolic pressures. Immunoreactive iNOS was found in endothelial cells, vascular smooth muscle cells and in the adventitia of small mesenteric arteries from CAL rats but not those from sham-operated rats. Third order mesenteric arteries (300-350 microm) were mounted in a small vessel pressure myograph. Endothelium-intact arteries from CAL rats were more responsive to phenylephrine (PE) than arteries from sham-operated rats (pD(2) value, CAL, 6.2+/-0.1; sham-operated, 5.9+/-0.1, P<0.05). Both the selective iNOS inhibitor, N-(3-(Aminomethyl) benzyl) acetamidine dihydrochloride (1400W; 10(-6) M) and the superoxide dismutase mimetic, Mn [III] tetrakis [1-methyl-4-pyridyl] porphyrin, (MnTMPyP; 10(-4) M) reversed the hyperesponsiveness (pD(2) values, 1400W, 5.9+/-0.1; MnTMPyP, 5.81+/-0.1, P<0.05). The NOS substrate, L-arginine (10(-3) M), reduced responsiveness of endothelium-denuded small mesenteric arteries from CAL rats (P<0.01). None of these drugs altered responses to PE in arteries from sham-operated rats. In summary, this study demonstrates that iNOS is expressed in mesenteric arteries from rats with CHF. However, instead of generating large quantities of NO, iNOS appears to be generating superoxide, perhaps because of a deficiency in its substrate, L-arginine. Increased superoxide generation from iNOS contributes to the hyperesponsive nature of endothelium-intact small mesenteric arteries from rats with CHF.
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PMID:Inducible nitric oxide synthase-derived superoxide contributes to hypereactivity in small mesenteric arteries from a rat model of chronic heart failure. 1096 65

ACE2, the first known human homologue of angiotensin-converting enzyme (ACE), was identified from 5' sequencing of a human heart failure ventricle cDNA library. ACE2 has an apparent signal peptide, a single metalloprotease active site, and a transmembrane domain. The metalloprotease catalytic domains of ACE2 and ACE are 42% identical, and comparison of the genomic structures indicates that the two genes arose through duplication. In contrast to the more ubiquitous ACE, ACE2 transcripts are found only in heart, kidney, and testis of 23 human tissues examined. Immunohistochemistry shows ACE2 protein predominantly in the endothelium of coronary and intrarenal vessels and in renal tubular epithelium. Active ACE2 enzyme is secreted from transfected cells by cleavage N-terminal to the transmembrane domain. Recombinant ACE2 hydrolyzes the carboxy terminal leucine from angiotensin I to generate angiotensin 1-9, which is converted to smaller angiotensin peptides by ACE in vitro and by cardiomyocytes in culture. ACE2 can also cleave des-Arg bradykinin and neurotensin but not bradykinin or 15 other vasoactive and hormonal peptides tested. ACE2 is not inhibited by lisinopril or captopril. The organ- and cell-specific expression of ACE2 and its unique cleavage of key vasoactive peptides suggest an essential role for ACE2 in the local renin-angiotensin system of the heart and kidney. The full text of this article is available at http://www. circresaha.org.
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PMID:A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. 2366 10

The role of endothelins (ET) in blood pressure elevation remains controversial. Data supporting involvement of the ET system in different forms of genetic and experimental hypertension in the rat has appeared in the literature in recent years. Production of endothelin (ET)-1 may be enhanced in several experimental rat models of hypertension. Examples of these exhibiting increased preproendothelin-1 mRNA or peptide in the vasculature include salt-sensitive forms like deoxycorticosterone (DOCA)-salt hypertension, DOCA-salt treated spontaneously hypertensive rat (SHR) and Dahl salt-sensitive rats, and other models like stroke-prone SHR, angiotensin II-infused rats and fructose-fed rats, and possibly 1-kidney 1 clip (1-K 1C) Goldblatt hypertensive rats. SHR, 2-kidney 1 clip (2-K 1C) Goldblatt hypertensive rats and chronic N(omega)-nitro-L-arginine methyl ester (L-NAME)-treated hypertensive rats do not appear to exhibit an ET-1 component. Significant vascular growth, and a hypotensive response and regression of vascular growth after treatment with an ET antagonist demonstrate the endothelin-dependency present in some hypertensive models. Severity of high blood pressure elevation, salt-sensitivity and insulin resistance may be common denominators of involvement of the ET system in hypertension. ET antagonism in hypertension may result in regression of vascular damage, prevention of stroke and renal failure and improvement of heart failure. Whether the same is true in human hypertension remains to be established.
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PMID:Endothelin: role in experimental hypertension. 1097 78

L-Arginine (Arg) is the substrate for the synthesis of nitric oxide (NO), the endothelium-derived relaxing factor essential for regulating vascular tone and hemodynamics. NO stimulates angiogenesis, but inhibits endothelin-1 release, leukocyte adhesion, platelet aggregation, superoxide generation, the expression of vascular cell adhesion molecules and monocyte chemotactic peptides, and smooth muscle cell proliferation. Arg exerts its vascular actions also through NO-independent effects, including membrane depolarization, syntheses of creatine, proline and polyamines, secretion of insulin, growth hormone, glucagon and prolactin, plasmin generation and fibrinogenolysis, superoxide scavenging and inhibition of leukocyte adhesion to nonendothelial matrix. Compelling evidence shows that enteral or parenteral administration of Arg reverses endothelial dysfunction associated with major cardiovascular risk factors (hypercholesterolemia, smoking, hypertension, diabetes, obesity/insulin resistance and aging) and ameliorates many common cardiovascular disorders (coronary and peripheral arterial disease, ischemia/reperfusion injury, and heart failure). Dietary Arg supplementation may represent a potentially novel nutritional strategy for preventing and treating cardiovascular disease.
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PMID:Arginine nutrition and cardiovascular function. 1105 97

Endothelial dysfunction contributes to the maintenance of peripheral vasoconstriction and abnormal vascular compliance in chronic heart failure. Endothelial dysfunction results in an imbalance between vasodilation and vasoconstriction, particularly when adjustments in blood flow are required. Recently, new factors have been recognized to determine endothelial dysfunction: a) disturbances of the L-arginine/nitric oxide pathway, either at the enzymatic or substrate level; b) increased synthesis of endothelin-1; c) microvessel structural remodeling; d) increased adhesive properties to blood cell components; and e) apoptotic cell injury. The understanding of the complex interplay among these factors is the basis for development of new targeted strategies to correct endothelial dysfunction in chronic heart failure.
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PMID:Endothelial dysfunction in chronic heart failure: some new basic mechanisms. 1106 61


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